Leukocytes use specialized mechanisms to emigrate from blood into tissues. Among them are selectins that mediate initial interactions with the vessel wall. These lectin-like protein receptors bind to mucin oligosaccharide ligands that are constitutively expressed in some locations (high endothelial venules) and inducible in others (inflamed endothelia). Selectin receptor-ligand bonds have unusual kinetic and mechanical properties that permit transient tethering and shear stress-dependent rolling. Upon capture, integrin activation triggers stable adhesion, bringing the cells into contact with factors that govern transmigration into tissues (e.g., chemokines and cytokines).
At a morphological level, analogies can be drawn between key steps in leukocyte emigration from blood and embryo attachment to the uterine wall. Implantation begins with apposition: the trophectoderm of the originally free-floating embryo lies adjacent to the uterine epithelium, but the blastocyst is easily dislodged. Soon thereafter, blastocyst adhesion to the uterine wall is stabilized and trophoblasts transmigrate across the uterine epithelium, a process that in humans buries the entire embryo beneath the uterine surface. Subsequent development depends on the ability of trophoblasts to adhere under conditions of shear stress created when these fetal cells breach uterine vessels, a process that diverts maternal blood flow to the placenta. At a molecular level, trophoblast adhesion from implantation onward is an integrin-dependent process that takes place in a chemokine- and cytokine-rich milieu analogous to the blood-vascular interface.
Reproductive failure is a serious problem that has been addressed clinically by various assisted reproductive technologies, including in vitro fertilization (IVF) and embryo transfer (ET). These procedures might be expected to yield exceptionally high conception rates as in vitro fertilization provides embryos that appear normal at a morphological level for transfer into a fully primed recipient. Despite these efforts the success rate of IVF/ET is less than ideal. In the published data for IVF/ET in the United States and Canada in 1994, there were 26,961 initiated cycles of standard IVF. Of these, 86.2% led to retrieval and of these 90.2% led to a transfer. However, the overall success rate in terms of clinical pregnancies was 22.7% per initiated cycle and a 29.1% pregnancy rate per transfer.
Additionally, there appears to be a high incidence of early pregnancy loss after in vitro fertilization with a biochemical pregnancy rate of 18% and a spontaneous abortion rate of 27%. Thus, it appears that the IVF technique has been well optimized but implantation failure may be the cause for a large number of losses with ET and this peri-implantational loss is an area of potential improvement. A major factor in the success rate of various assisted reproductive technologies is endometrial receptivity, a transient state that must be coordinated with embryo development to implantation-competent blastocysts.
Improved methods of contraception, that is prevention of fertilization or implantation of the fertilized egg, are needed particularly in light of increasing population pressure. Many efforts have been made to provide improved contraception utilizing devices or hormonal therapy for females as for example as set forth in U.S. Pat. Nos. 5,771,900; 5,756,115; 5,583,129; 4,922,928; 4,703,752; and 4,564,362 and the references cited therein. However, they are not always successful in providing contraception and improved methods are needed. Progesterone receptor antagonists (such as RU486) alter uterine biochemistry but this alteration is used to induce abortion or as a morning-after pill to prevent implantation. It would be useful to have other methods available that can change uterine receptivity biochemically.
There is a need in the art for methods for determining endometrial receptivity to embryo implantation. There is also a need in the art for additional methods of inhibiting pregnancy. There is also a need in the art for non-invasive methods for evaluating embryo quality prior to transfer in assisted reproductive technologies. There is also a need for markers that identify a woman's relative risk of experiencing a spontaneous abortion early in pregnancy. The present invention addresses these needs.
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